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Pharmacophore-Directed Retrosynthesis Applied to Ophiobolin A: Simplified Bicyclic Derivatives Displaying Anticancer Activity.

ABSTRACT: Pharmacophore-directed retrosynthesis applied to ophiobolin A led to bicyclic derivatives that were synthesized and display anticancer activity. Key features of the ultimate defensive synthetic strategy include a Michael addition/facially selective protonation sequence to set the critical C6 stereocenter and a ring-closing metathesis to form the cyclooctene. Cytotoxicity assays toward a breast cancer cell line (MDA-MB-231) confirm the anticipated importance of structural complexity for selectivity (vs MCF10A cells) while C3 variations modulate stability.

SUBMITTER: Tao Y

PROVIDER: S-EPMC7655722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Enzymes synthesize complex natural products effortlessly by catalyzing chemo-, regio-, and enantio-selective transformations. Further, biocatalytic processes are increasingly replacing conventional organic synthesis steps because they use mild solvents, avoid the use of metals, and reduce overall non-biodegradable waste. Here, we present a single-step retrosynthesis search algorithm to facilitate enzymatic synthesis of natural product analogs. First, we develop a tool, RDEnzyme, capable of extracting and applying stereochemically consistent enzymatic reaction templates, i.e., subgraph patterns that describe the changes in connectivity between a product molecule and its corresponding reactant(s). Using RDEnzyme, we demonstrate that molecular similarity is an effective metric to propose retrosynthetic disconnections based on analogy to precedent enzymatic reactions in UniProt/RHEA. Using ∼5500 reactions from RHEA as a knowledge base, the recorded reactants to the product are among the top 10 proposed suggestions in 71% of ∼700 test reactions. Second, we trained a statistical model capable of discriminating between reaction pairs belonging to homologous enzymes and evolutionarily distant enzymes using ∼30 000 reaction pairs from SwissProt as a knowledge base. This model is capable of understanding patterns in enzyme promiscuity to evaluate the likelihood of experimental evolution success. By recursively applying the similarity-based single-step retrosynthesis and evolution prediction workflow, we successfully plan the enzymatic synthesis routes for both active pharmaceutical ingredients (e.g. Islatravir, Molnupiravir) and commodity chemicals (e.g. 1,4-butanediol, branched-chain higher alcohols/biofuels), in a retrospective fashion. Through the development and demonstration of the single-step enzymatic retrosynthesis strategy using natural transformations, our approach provides a first step towards solving the challenging problem of incorporating both enzyme- and organic-chemistry based transformations into a computer aided synthesis planning workflow.

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Pharmacophore-Directed Retrosynthesis Applied to Ophiobolin A: Simplified Bicyclic Derivatives Displaying Anticancer Activity.

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